The collection of bacterial, viral, and fungal commensal microorganisms that reside within and on the human body are collectively known as the human microbiome. The bacterial subset of the human microbiome plays an important role in host nutrient acquisition, development, immunological homeostasis, neurological health, and protection against pathogens (LeBlanc et al. Curr. Opin. Biotechnol. (2013) 24(2): 160-168; Hooper et al. Science (2012) 336(6086): 1268-1273; Hughes et al. Am. J. Gastroenterol. (2013) 108(7): 1066-1074). As the largest reservoir of mammalian commensals, bacteria residing in the gastrointestinal (GI) tract influence nearly all of these aspects of human biology (Blaser J. Clin. Invest. (2014) 124(10): 4162-4165). Consequently, perturbation of the normal bacterial populations within the GI niche, a state known as dysbiosis, can predispose humans to a variety of diseases.
Clostridium difficile infection (CDI) arises after intestinal colonization by the anaerobic spore-forming Gram-positive pathogen Clostridium difficile. Upon colonization of the GI tract, C. difficile produces toxins which causes diarrhea and may ultimately lead to death. This illness is the most common identifiable cause of nosocomial diarrhea and is thought to arise as a direct result of dysbiosis (Calfee Geriatrics (2008) 63: 10-21; Shannon-Lowe et al BMJ (2010) 340: c1296). Not surprisingly, usage of nearly all classes of antibiotics has been associated with CDI, presumably by inducing dysbiosis in the GI tract and thereby enabling C. difficile outgrowth. The Center for Disease Control currently classifies CDI as a public health threat requiring immediate and aggressive action because of its natural resistance to many drugs and the emergence of a fluoroquinolone-resistant strain that is now prevalent throughout North America and Europe. C. difficile was responsible for almost half a million infections and was associated with approximately 29,000 deaths in 2011 (Lessa et al. NEJM 2015, 372; 825-834).
The antibiotics metronidazole, vancomycin, and fidaxomicin are the current therapeutic options for treatment of CDI. However, metronidazole is inadequate because of decreased response rates and neither metronidazole nor vancomycin prevent disease recurrence, with up to 30% of patients initially responding experiencing a clinical recurrence after antibiotic cessation (Miller Expert Opin. Pharmacother. (2010) 11: 1569-1578). Fidaxomicin has been shown to be superior to vancomycin in preventing recurrent CDI (Mullane Ther. Adv. Chronic Dis. (2014) 5(2): 69-84). Because of its narrow spectrum of activity, fidaxomicin is thought to enable normal microbiome repopulation of the gut following dysbiosis and CDI, thereby lowering the likelihood of recurrent disease (Tannock et al. Microbiology (2010) 156 (Pt 11): 3354-3359; Louie et al. Clin. Infect. Dis. (2012) 55 Suppl. 2: S132-142). Nonetheless, 14% of fidaxomicin-treated patients experience CDI relapse and mutations conferring reduced sensitivity have already been reported (Eyre et al. J. Infect. Dis. (2014) 209(9): 1446-1451).
Because the risk of recurrent CDI is heightened by antibiotic use and C. difficile spores are inherently recalcitrant to the available chemotherapeutic arsenal, alternative therapeutic modalities are being pursued for the treatment of CDI. Fecal microbiota transplantation (FMT) is one such modality that has shown efficacy against CDI (Khoruts et al. Immunol. Lett. (2014) 162(2): 77-81; van Nood et al. N. Engl. J. Med. (2013) 368(5): 407-415). To date, results of FMT studies for the treatment of CDI, have reported cure rates up to 90% in three randomized controlled studies (Cammarota et al. Alimen. Pharmacol. Therap. (2015) 41(9): 835-843; Kassam et al. Am. J. Gastroenterol. (2013) 108(4): 500-508; van Nood et al. N. Engl. J. Med. (2013) 368(5): 407-415; Youngster et al. Infec. Dis. Soc. Am. (2014) 58(11): 1515-1522).
Despite the success of FMT, this therapeutic approach is not without risks and logistical concerns. Selection of FMT donors is critical and challenging. When FMT donor recruitment is performed with stringent screening and standardization protocols, most prospective donors fail this process. Only 6-10% of prospective FMT donors qualify, with the majority of failures arising from asymptomatic carriage of GI pathogens (Paramsothy et al. Inflamm. Bowel Dis. (2015) 21(7): 1600-1606; Borody et al. Curr. Opin. Gastroenterol. (2014) 30(10): 97-105; Burns et al. Gastroenterology (2015) 148: S96-S97; Surawicz Ann. Intern. Med. (2015) 162(9): 662-663). Furthermore, variation between donors may lead to variation in FMT efficacy. In addition, the risk of transmission of even non-infectious illnesses may be heightened by FMT. Indeed, significant weight gain has been reported in a patient who received an FMT from an overweight stool donor (Alang et al. Open Forum Infect. Dis. (Winter 2015) 2(1)).